Updates in the Treatment of Knee Osteoarthritis

Knee osteoarthritis (OA) is an inflammatory and degenerative condition resulting in articular cartilage destruction and functional loss. Its prevalence has grown considerably due to increased life expectancy and obesity, and its diagnosis relies on evaluation, medical examination, and confirmation by supplementary radiographic images. Knee OA is multifactorial and influenced by several local, systemic, and external aspects. In addition, its progress and therapeutic responses highly depend on the characteristics of each subject. The initial recommendation is drug treatment and alternative therapies to improve quality of life. However, if these treatments are unsuccessful, one must consider surgical treatment. Surgical options include arthroscopies, osteotomies, and partial and total arthroplasties, while non-surgical treatments include medications and alternative therapies such as infiltrations, acupuncture, and physical exercise. It is worth highlighting that biomarkers can be a significant strategy for early disease detection, assessment of disease activity, prediction of prognosis, and monitoring a better response to therapy. Nevertheless, this topic must be the focus of further research to confirm its findings.


Introduction
Osteoarthritis (OA) causes cartilage degradation, bone remodeling, osteophyte formation, and synovial inflammation, resulting in pain, stiffness, edema, and loss of joint function.It is a significant cause of disability among adults and older subjects. 1,2Populational aging and the progressively higher prevalence of obesity are increasing the incidence of this disease. 2he most common knee disease, OA may result in repeated joint effusion and functional limitation. 3A slow and steady understanding of the pathophysiology of knee OA has been witnessed in recent decades.However, gaps regarding its pathogenesis remain, negatively impacting drug development and innovation.The lack of new medications and modifying drugs for knee OA treatment highlights the need for lifestyle changes to delay surgical intervention. 4][7] Additionally, the use of biological therapies has been increasing as alternatives to OA treatment, particularly intra-articular (IA) infiltrations.Hyaluronic acid (HA) is widely known as a safe conservative treatment for OA in the knee and other joints. 8It provides pain relief, stimulates synovial fluid production, and cushions and lubricates joint surfaces. 9 growing body of scientific literature supports the use of IA infiltrations with HA for knee OA over placebo and other therapies.Acharya et al. 10 analyzed the effectiveness of IA with HA regarding pain, functional capacity, and quality of life in patients with early primary knee OA.These authors 10 reported short-term beneficial effects (up to one year), observing a decreasing trend in pain intensity and a progressive improvement in physical functioning and health-related quality of life after a single intervention.
Knee OA is multifactorial and influenced by several local, systemic, and external aspects.In addition, its progress and therapeutic responses highly depend on the characteristics of each subject.To better understand this condition, the present study aimed to gather information about its pathophysiology, clinical diagnosis, and updates on its treatment.

Pathophysiology of Knee Osteoarthritis
Osteoarthritis results from complex biological processes affecting cartilage, bone, ligaments, synovium, meniscus, periarticular fat, and muscles.It usually presents with joint space narrowing (JSN) due to articular cartilage loss, meniscal degeneration, and bone changes, including subchondral bone sclerosis and osteophytes. 11,12he biomechanical environment can influence OA development.Varus alignment shifts the load medially, increasing the risk of knee OA in the medial compartment, while valgus alignment shifts the load laterally, triggering OA in the lateral compartment.Additionally, previous knee trauma increases the risk of OA by 3.86 times. 13echanical overload often accounts for starting the process of cartilage damage, which later evolves into inflammation, causing joint degradation.The primary precursors of this inflammation process include interleukin-1 (IL-1) and tumor necrosis factor (TNF).These molecules maximize the expression of metalloproteinases and nitric oxide, the main catabolic agents synthesized by chondrocytes in response to injury. 14Therefore, OA is an inflammatory disease of the entire synovial joint, comprising the mechanical and

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structural degeneration of the articular cartilage and triggering functional changes in the entire joint. 4he development of OA is slow, and the pain can be progressive; 12 OA is a major cause of pain and disability, directly affecting quality of life. 2 It may result from several factors, including age, body weight disorders, knee joint overload, prolonged hyperflexion, and axis deviations. 3ccording to Primorac et al., 15 the prevalence of knee OA is higher in adults aged !60 years, representing one of the most significant causes of disability among elderly subjects.In addition, the risk is higher in obese people (body mass index [BMI] !30 kg/m 2 ) than in non-obese people (19.7% versus 10.9% respectively).

Clinical Diagnosis and Classification Systems
The diagnosis is initially clinical, based on symptoms of pain, stiffness, and functional limitations, as well as a thorough physical examination with crepitus, pain, restricted mobility, joint sensitivity, and bone enlargement observation. 2eight-bearing knee radiographs help confirm the diagnosis and enable the classification of knee OA and the observation of structural damage.In addition, they improve specificity when osteophytes or JSN are present. 16agnetic resonance imaging (MRI) reveals the effects of knee OA on the cartilage, meniscus, synovial membrane, and subchondral bone.Moreover, a tool developed by Cho et al. 17 uses infrared immunoliposomes against type-II collagen antibodies for early OA diagnosis and treatment.
Classifications are critical in knee surgery since effective classification systems can guide prognostic estimates.The recent publication by Pires et al. 18 , "Classifications and flowcharts in knee surgery," is a Brazilian reference study that combines several classifications, flowcharts, and questionnaires to aid in the diagnosis and decision-making by specialists.
Following the classifications for degenerative lesions, 18 the most common method for radiographic definition is the Kellgren-Lawrence classification system.The overall joint score classifies OA as follows: grade 0 represents no pathological findings; grade 1 indicates potential JSN and edge osteophytes; grade 2 indicates potential JSN and definitive osteophytes; grade 3 establishes the presence of JSN, multiple osteophytes, some subchondral sclerosis, and potential bone contour deformity; and grade 4 denotes notable JSN, severe subchondral sclerosis, definitive bone contour deformity, and the presence of large osteophytes. 19

Clinical Examination and Imaging
About 40% of the population aged over 65 years has symptomatic knee OA.Early detection and intervention are paramount to reduce morbidity and disability, resulting in better self-reliance.Radiography is the first investigation of choice for OA patients presenting with knee pain.Communitybased studies 19 have shown that 40% to 80% of subjects with OA and radiographic knee changes are symptomatic, and that severe radiographic findings are associated with reports of pain that is more intense.However, there is a high degree of discordance between clinical and radiographic findings, and radiological OA classification is inaccurate in the early stages.The multifactorial origin of pain may explain this discrepancy between pain and radiographic findings. 19he discrepancy between the physical and imaging examinations, especially concerning symptoms, can be explained by the propensity of some OA patients to develop sensitized central nociceptive circuits that increase pain during various states of aggression to peripheral tissues. 20,21his abnormality, known as central sensitization, is a maladaptive nociceptive process involving complex neuroplastic changes amplifying pain at multiple levels of the neuraxis. 20ince central sensitization correlates with the activation of neural circuits implicated in the descending facilitation of pain and, as such, is a risk factor for the development and maintenance of chronic pain, it is essential to identify which patients present abnormal responses to relevant painful stimuli.
According to the literature, several conditions can affect biomarker levels.Some evidence suggests that physical activity, hormonal levels, medications, and the sex of the patient may result in biomarker level fluctuations.Tanishi et al. 22 observed that uCTX-II levels differed significantly between men and women and in premenopausal and postmenopausal women.
Due to its ability to distinguish between healthy subjects and OA patients, another potential biochemical marker widely reported in the literature is COMP, 23 which also has some potential prognostic capabilities.Although some studies have reported conflicting results, a meta-analysis 23 showed that these biochemical markers (that is, COMP and CTX-II) may be effective to diagnose OA, assess prognosis progression, and differentiate between healthy subjects and those with OA.
The emergence of these biomarkers is relatively recent, and the best strategies for their application remain under study, in terms of technology and medical research, with the goal of developing reliable detection methods.

Treatments
The first-line treatment for knee OA does not involve surgical interventions, and management may be multimodal.However, if these therapies are unsuccessful, one must consider surgical treatment.Although OA has no cure, several surgical and nonsurgical treatment options are available to help manage pain and maintain the health of the affected patients. 12he following section will discuss the most widespread treatments according to their current level of recommendation.

Search Strategy
A bibliographical survey was performed in PubMed, MED-LINE, and Embase for studies published until February 20, 2023.The descriptors included Updates; Knee Osteoarthrosis, and Treatment, and the filters included Randomized Controlled Trial, Randomized Clinical Trial, Meta-Analysis, Systematic Reviews, and Cohort.

Eligibility and Selection Criteria
The retrieved studies met the following inclusion criteria: • Studies related to the proposed topic; • Studies with level of evidence of I to III; • Articles in English, Spanish, and Portuguese; • Research carried out on humans; • Articles available in full versions.
The exclusion criterium was the following: • Studies with a low level of evidence, such as a simple case reports.

Identification of Studies and Characteristics
Following the search strategy, we found 41 studies with the aforementioned descriptors.These studies underwent a new assessment regarding their design, relevance, study type filters, and inclusion criteria.This assessment resulted in eight studies available in full and included according to category and type of treatment.

Surgical Treatments Arthroscopy
Arthroscopy removes debris and crystals released in the joint cavity affected by OA, regularizing the joint surface. 24A literature survey retrieved 26 systematic reviews and meta-analyses describing the results of 6,418 patients with a mean age of 47 AE 19 years (►Figs. 1 and 2).Arthroscopic surgery for degenerative knee disease has been the focus of several recently published randomized clinical trials (RCTs), high-quality systematic reviews, and meta-analyses.Although pioneering studies have demonstrated that minimally-invasive arthroscopy had promising results, their strength was insufficient for a recommendation.2][13][14][15][16][17]25 A recent systematic review 11 published in the British Medical Journal strongly recommended against arthroscopy in patients with degenerative knee disease, emphasizing the importance of fully utilizing appropriate conservative treatment options.In particular, the recommendations directed clinicians to maximize exercise therapy, as the results presented in RCTs demonstrate that arthroscopic surgeries are not superior to complete physiotherapy protocols. 11][28] In a prospective cohort, Navarro et al. 29 aimed to ascertain whether knee arthroscopy to treat meniscal damage by OA delayed knee replacement compared with physiotherapy alone.The main findings were that the cumulative incidence of knee replacement was modest but significantly higher for subjects undergoing arthroscopy than physical therapy alone (risk ratio: 1.30; 95% confidence interval: 1. 17-1.44; p < 0.001).The authors 29 concluded that, for patients with meniscal damage complicated by OA, those who underwent arthroscopy were 30% more likely to have partial or total knee replacement surgery at any point during follow-up compared with those undergoing physical therapy alone.

Indications
For all these reasons, many researchers limit the indications for arthroscopy.The technique still presents advantages in the early stages of OA, in which movement limitation is mechanical, and there are free articular bodies.However, physical therapy must accompany arthroscopy. 26or Zhao et al., 27 arthroscopy presents no advantages over the several surgical options due to the weak and scarce evidence supporting its application.Likewise, recent studies suggest that arthroscopy may not be beneficial for patients with chronic degenerative meniscal tears, emphasizing the importance of conservative follow-up for the management of knee OA. 28 The small and inconsequential benefit observed in interventions including arthroscopy for the degenerated knee is time-limited and absent within one to two years after surgery.Knee arthroscopy is associated with harm.Together, these findings do not support arthroscopic surgery for middle-aged or elderly patients with knee pain with or without signs of OA.

Arthroplasty
Arthroplasty is a surgical option to treat patients with extreme cases of knee joint degeneration; it can be total (total knee replacement, TKR) or unicompartmental (partial knee replacement, PKR), depending on the degree of OA. 30 In the literature survey, we found 22 systematic reviews and meta-analyses describing the outcomes of 14,095 patients with a mean age of 58 AE 21 years (►Figs.3 and 4).
For OA limited to a single compartment, PKR or unloading osteotomy may be an option.Their recommendation includes young, active patients because of the risks and limited durability of TKR.In contrast, TKR is a common, safe method in elderly patients with advanced knee OA and the gold-standard surgical treatment for advanced cases. 30n RCT 31 demonstrated that TKR is superior to nonsurgical treatment alone in relieving pain in patients with moderate to severe knee OA and in improving function and quality of life after one year.However, both groups presented clinically relevant improvements, and patients undergoing TKR had more severe side effects.Furthermore, resection of the interpatellar fat pad during TKR is the subject of ongoing debate, with no clear consensus. 31

Indications
The indication for TKR includes patients with advanced joint degeneration process and subjects older than 60 years.It is also the gold-standard treatment in this last group of patients.The indication for PKR includes young, active patients due to the risks and limited durability of TKR.

Osteotomy
High tibial osteotomy (HTO) has been used for over sixty years as a clinical exercise.This technique, performed around the knee, aims to maintain a regular anatomical structure, achieve better functional recovery of the knee joint, attenuate joint softness, reduce the cartilage degeneration rate, and prevent or postpone joint replacement. 32This technique relies on a controlled osteotomy, transferring the weightbearing axis from the degenerate compartment to the healthy compartment to realign the lower limb. 33As a result, this procedure interferes little with soft tissues and often has no harmful effects on the stability and mobility of the knee joint. 34n the literature survey, we found 19 systematic reviews and meta-analyses describing the outcomes of 8,412 patients with a mean age of 51 AE 7 years (►Figs. 5and 6).
High tibial osteotomy comprises two main techniques: closing-wedge HTO (CWHTO) and opening-wedge OTA (OWHTO). 34These procedures may occur proximal or distal to the knee joint.In general, if knee OA is in the medial compartment, HTO is most commonly performed by operating on the upper tibia.In OA affecting the lateral compartment, HTO is usually performed on the lower femur.However, one must always measure the distal lateral femoral angles and the medial proximal tibial angle to optimize the correct osteotomy location and whether it will be an addition  or subtraction following the principles described by Paley and Tetsworth. 35he indication for HTO includes young, active subjects, often under the age 50.Several factors may influence HTO outcomes. 36Valeiy Evgenievich et al. 37 demonstrated a greater efficiency of HTO in the second stage of knee OA than in the third stage.These authors also noted that age and correction angle do not affect the outcome, but high BMI is associated with worse results and complications.The literature heterogeneously reports its imprecision, including lower functional outcomes, OA progression, and conversion to arthroplasty.
Lastly, HTO is an autonomous treatment, but the process of limb alignment intrinsically relates to the joint and stabilizing knee structures.Therefore, one must consider combining HTO with other osteotomies and arthroplasties.In addition, it may be a treatment strategy in procedures aiming to stabilize the knee and restore the cartilage.

Indications
High tibial osteotomy is suitable for young patients, especially those with OA and partially preserved cartilage.For knee biomechanics correction, the highest efficacy of HTO  occurs in patients with second-stage knee OA compared to the third stage.
Proximal fibular osteotomy (PFO) is more suitable for patients with many complications and low surgical tolerance, as it can reduce operative time, intraoperative bleeding, hospitalization time, and postoperative complications, with some advantages.

Non-surgical Treatments Pharmacological Therapies
Pharmacological therapy for OA is purely symptomatic and, in most cases, successfully assures the maintenance of the patient's mobility.It may include paracetamol, topical or oral non-steroidal anti-inflammatory drugs (NSAIDs), or intra-articular corticosteroids.Although paracetamol is a drug of considerable efficacy, safety, and low cost, the Osteoarthritis Research Society International (OARSI) guidelines recommend its administration in conservative doses and periods because of the increased risk of gastrointestinal and liver disorders. 38n parallel, NSAIDs are the first-line pharmacological treatment for OA, with evidence proven by placebo-controlled trials.Topical NSAIDs often result in less gastrointestinal toxicity than oral NSAIDs.However, one must discuss alternatives to NSAIDs for patients who are susceptible or present risk factors for the adverse effects of the medication.It is worth highlighting that drugs should complement, not replace, the non-pharmacological treatment.

Indications
Patients with symptomatic OA.

Intra-articular Infiltrations
Biological therapies have been increasingly sought after as alternatives for OA treatment.Intra-articular infiltrations stand out as treatments approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). 39These infiltrations enable the administration of a concentrated drug dosage and its distribution locally and throughout the joint.Thus, these drugs can access places that it would not with oral intake.Furthermore, IA infiltrations offer much better bioavailability and limit the systemic drug passage, reducing the risk of side effects. 39,40dications Intra-articular infiltrations are an adjuvant therapy for OA treatment, especially in patients already under chronic systemic treatment, such as elderly subjects.

Hyaluronic Acid (HA)
A natural substance found in the synovial fluid surrounding joints, HA is a polysaccharide from the glycosaminoglycan family that smoothly reduces attrition during movement, cushioning the shock between loads.Subjects with OA present lower HA levels.Therefore, exogenous HA infiltrations can help restore the elastic and viscous properties of the synovial fluid, minimizing pain and improving function. 12Hyaluronic acid also increases shock absorption, provides synovial fluid lubrication, and acts on joint nociceptive response with reflex quadriceps muscle inhibition.The anti-inflammatory, analgesic, and chondroprotective action of HA results from the modulation of intra-and extracellular inflammation cascades.In addition to being safe and effective in treating pain due to patellar chondropathy, it improves mobility and slows down the degenerative process. 8ussu et al. 41 investigated the treatment of knee OA with HA derivative infiltrations and observed satisfactory outcomes six months after the procedure, showing therapeutic efficiency in treating moderate to severe knee OA.In contrast, HA application alone yielded less significant outcomes concerning pain in patients under treatment when compared to HA combined with platelet-rich plasma (PRP). 42owever, some authors mention the occurrence of allergic side effects related to the product's origin.Pain and swelling after injection may result from the high molecular weight and different pharmaceutical formulations of HA.The other major challenge of HA treatment is the need for multiple injections to obtain the desired efficacy.As such, multiple injections could result in more cost, pain, and potential infection.Therefore, updates and innovations in single-dose high molecular weight medications have gained prominence in the therapeutic arsenal, with good outcomes in the joint functional status.

Indications
Infiltration of HA is an adjuvant therapy for OA treatment, mainly regarding symptoms and function, but its evidence still lacks scientific strength.

Platelet-Rich Plasma (PRP)
A blood-derived product with a high platelet concentration in a small plasma volume, PRP plays a role in the release of several growth factors (insulin-like growth factor 1 [IGF-1], plateletderived growth factor [PDGF], epidermal growth factor [EGF], vascular epidermal growth factor [VEGF], and transforming growth factor-β [TGF-β]).All of these molecules act in the initial phase of healing and tissue regeneration.The type of growth factors in PRP and their levels vary in each subject.Moreover, its mechanism is not fully understood, and it is difficult to determine the effects of each type of factor. 43The use of PRP in studies has already demonstrated considerable and complex biological activities, such as cell proliferation, anti-apoptotic activity, cartilage regeneration, collagen synthesis, and angiogenesis maximization. 43aita et al. 44 studied 517 patients receiving 3 PRP injections and analyzed the outcomes per the severity of knee OA.The authors state that the therapy is approximately 60% effective depending on the severity of the disease.Furthermore, this efficacy is independent of age, gender, body weight, or platelet count. 44,45Knop et al., 46 based on RCTs, reported that PRP significantly improves joint pain and function when compared with HA, including sustained response for up to two years in milder knee OA cases.
Furthermore, it is worth highlighting that the Brazilian Federal Council of Medicine (Conselho Federal de Medicinas, CFM, in Portuguese), in its Resolution no.2,128/2015, considers PRP an experimental procedure and only allows its use in clinical trials within the protocols of the Brazilian Research Ethics Committee/Research Ethics National Committee (Comitês de Ética em Pesquisa/Comissão Nacional de Ética em Pesquisa CEP/CONEP, in Portuguese) system.Likewise, the Brazilian National Health Regulatory Agency (Agência Nacional de Vigilância Sanitária, ANVISA, in Portuguese), in Technical Note no.12/2015, ratified the experimental use of PRP as a product with no proven therapeutic utility, requiring more scientific evidence for clinical use.

Indications
Platelet-rich plasma is an adjuvant therapy for OA treatment, mainly concerning pain; it significantly improves pain and joint function compared to HA, including sustained response for up to two years in milder cases of knee OA.

Stem Cells
Stem-cell therapy emerges as a milestone in regenerative medicine for knee OA treatment, and its potential is deemed high. 47Mesenchymal stromal/stem cells (MSCs), such as bone marrow, adipose tissue, and synovium stem cells, aid in damaged cartilage regeneration and are reportedly safe. 48n a trial, 49 nine patients diagnosed with knee OA received a single injection of adipose-derived mesenchymal stem cells (AD-MSCs) at a concentration of 0.5-1.0Â 10 7 cells.The follow-up period was of 18 months.The results showed significant improvement in all aspects evaluated in the initial six months, being sustained up to the end of the treatment. 49n RCT by Chen et al. 50assessed the safety and efficacy of allogeneic adipose-derived stem cells (ADSCs; ELIXCYTE, UnicoCell Biomed Co., Ltd., Taipei, Taiwan) infiltration for knee OA treatment.Patients either received one dose of HA or three doses of ELIXCYTE.ELIXCYTE was more effective than HA, providing an early pain reduction and functional improvements. 50lthough studies have shown that MSCs yield promising results in improving patients' clinical and structural conditions, there is still limited evidence, a lack of procedural standardization, and no long-term advantages.

Indications
Mesenchymal stem cells are adjuvant therapy for OA treatment, mainly for pain.

Prolotherapy with dextrose
The fundamental principle of dextrose prolotherapy is the injection of small volumes of an irritating solution into areas of painful attachments (ligaments, tendons, and adjacent joint spaces) at several treatment sessions.The mechanism of action remains unclear.However, hypotheses suggest that prolotherapy stimulates local healing of chronically-damaged extra-and intra-articular tissue, but with no definitive evidence.The literature 51 reports that prolotherapy injections may be appropriate to treat the multifactorial cause of OA-related knee pain.

Indications
Dextrose prolotherapy is an adjuvant method for OA treatment, mainly concerning pain, but there is no current evidence about it.

Genicular Nerve Block
In the literature survey, we retrieved seven randomized studies and one systematic review.
Genicular nerve block (GNB) is a therapeutic alternative aimed at blocking the three sensory nerves of the knee: the lateral and medial superior genicular nerve and the medial inferior genicular nerve.The block hinders the transmission of pain to the central nervous system and results in functional improvement. 52Ultrasound can guide GNB, enabling direct visualization of the structures and realtime control of the anesthetic application. 53Thus, the block is performed more efficiently, generating lower latency, dependence on anatomical information, and lower use of the anesthetic solution, in addition to providing greater safety. 54 study 54 analyzed four elderly patients with advanced knee OA, presenting limited movement and chronic pain, who underwent ultrasound-guided GNB.The outcomes were satisfactory, with a significant improvement in pain and functional capacity and no complications. 54A twelve-week analysis 55 compared the efficiency of IA block therapy and GNB.Both techniques resulted in satisfactory outcomes, minimizing pain, improving nighttime sleep quality, and facilitating the performance of daily activities.However, the study reports that GNB represents a safer, minimallyinvasive, and highly-efficient alternative.55

Indications
There is reasonable evidence to at least target the superior medial genicular nerve, the inferior medial genicular nerve, and the inferior medial genicular nerve using local anesthetics, corticosteroids, or alcohol to reduce pain and improve knee function in patients with chronic knee OA under ultrasound guidance.The procedure is safe, but more research is needed to determine the ideal interventional approach.

Acupuncture
Acupuncture is a well-known technique to treat several conditions by inserting fine needles in specific anatomical points. 56Studies on acupuncture to minimize knee OA pain and provide functional rehabilitation have been increasing, demonstrating that this therapy acts to mitigate symptoms due to the activation of various chemical elements that present bioactivity through peripheral, spinal, and supraspinal mechanisms. 57eixeira et al. 6 evaluated the treatment of two patients with knee OA through one weekly, thirty-minute acupuncture session (for six weeks) at four local points.The researchers 6 reported pain minimization and increased range and mobility of the knee joint flexion, demonstrating that the technique is efficient as an alternative or complementary treatment for OA, even in a short period.In general, acupuncture can improve the subjective perception of the quality of life of patients with OA, enabling a better performance of daily activities.Nevertheless, one must consider factors such as the number and duration of acupuncture sessions, the patient's health status, and the time of prevalence of the disease.

Indications
Acupuncture plays a role in OA treatment, especially concerning pain.

Physical Exercises
Clinical guidelines for knee OA management suggest that patients should receive a core set of non-pharmacological interventions, including education, weight loss, and lowimpact exercise (strengthening, cardiovascular exercise, and/or mind-body exercises, such as yoga or tai chi). 58A recent systematic review 59 evaluated different RCTs on the effectiveness of land-based physical activities for patients with knee OA.In these studies, patients with this joint condition either underwent exercises or did not perform exercises or receive any treatment.The authors 59 found that the group performing land-based physical activities consistently presented reduced pain and improved their physical shape and quality of life.

Indications
Current research 60 indicates that aerobic activity for 150 minutes a week at moderate intensity, moderate/vigorous physical activity, or muscle strengthening exercises 2 days a week bring many benefits to subjects with preexisting knee OA.

Miscellaneous Interventions
Another therapeutic resource is the lateral wedge insole.Recent research 61 concluded that a customized external orthosis (fixed below the sole) resulted in a higher improvement in pain and functional status than a control orthosis.Likewise, varus or valgus correction orthoses (altering biomechanics) and shifting the load to the least compromised compartment are alternatives to gain function and improve pain.

Final Considerations
Knee OA is a highly prevalent and disabling disease.In the past few years, we gained significant information about the cause and pathogenesis of OA, leading to a new era in OA therapy.However, management should not be generalized and requires adaptation according to each subject, enabling the establishment of the ideal intervention for each case.
Changing lifestyles, practicing physical exercise, and acupuncture, among others, are minimally-invasive methods for initial treatment, leaving surgical procedures as alternatives for cases in which these methods do not provide satisfactory responses.Therefore, the search for disease-modifying drugs for OA treatment has become a priority in orthopedics.
Hyaluronic acid is safe and effective in treating OA-related pain in the knee and other joints, confirming that it may have some disease-modifying properties.
In conclusion, further studies on this topic are required to achieve better scientific knowledge and then understand and fill the remaining gaps.

Fig. 1
Fig.1Graphical representation of the outcomes of studies assessing arthroscopy for the treatment of knee degenerative disease.

Fig. 2
Fig. 2 Temporal description of the literature included by year of publication.

Fig. 4
Fig.4Temporal description of the literature included by year of publication.

Fig. 3
Fig.3Graphical representation of the outcomes of studies assessing (total or partial) arthroplasty for the treatment of knee degenerative disease.

Fig. 6
Fig. 6 Temporal description of the literature included by year of publication.

Fig. 5
Fig. 5 Graphical representation of the outcomes of studies assessing osteotomy for the treatment of knee degenerative disease.